Overexpression of the p185 ErbB2 receptor tyrosine kinase (RTK) is tbund in - 30% of human breast carcinomas, leading to detrimental consequences. We previously demonstrated that ErbB2 overexpression protects human breast cancer cells from apoptosis induced by taxol, a microtubule-stabilizing agent. When breast cancer cells are exposed to taxol, cells enter M phase with inappropriate Cdc2 activation, undergo mitotic catastrophe, and die. Cdc2 activation is required for taxol-induced apoptosis but overexpression of ErbB2 inhibits Cdc2 activation, thereby delaying cell entry into M phase in the presence of taxol, thus cells may escape from mitotic catastrophe. Recently, we have found that in ErbB2-overexpressing breast cancer cells, 1) ErbB2 transcriptionally upregulates p21Cip1, which inhibits Cdc2 activation; 2) ErbB2 associates with Cdc2/CycIin B, and induces Cdc2 inhibitory phosphorylation on tyrosine (Y) 15 of Cdc2 (Cdc2-Y15-p); 3) ErbB2 upregulates survivin, an inhibitor of apoptosis (IAP) expressed at G2/M and localized to the mitotic apparatus that is required to preserve cell viability at cell division. We, therefore, hypothesize that the effects of ErbB2 on multiple G2/M regulators (p21Cipl upregulation, Cdc2-Y15-p, survivin upregulation, etc.) can lead to G2/M deregulation that contributes to antiapoptosis. To test this hypothesis, we propose three Specific Aims. First, we will elucidate mechanisms of ErbB2-mediated transcriptional upregulation of p21Cip1 that confers Cdc2 inhibition and antiapoptosis. Second, we will examine Cdc2-Yl 5-p by ErbB2 and its contribution to M phase deregulation and antiapoptosis. Third, we will investigate whether and how survivin contributes to ErbB2-mediated mitosis deregulation and antiapoptosis. These studies will provide new links from the ErbB2 RTK to mitosis regulation and antiapoptosis. The knowledge obtained will be useful for designing new strategies to sensitize ErbB2 overexpressing breast cancer cells to taxol and other agents targeting Ga/M phase of the cell cycle.